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1.
Ann Oncol ; 29(12): 2356-2362, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30481267

RESUMEN

Background: Following neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse. Patients and methods: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n = 202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort. Results: Regression and clustering analysis of MAGIC patients defined a seven-Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P < 0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P = 0.02; HR 3.6 in high-risk group, P = 0.0002), and not prognostic in surgery only patients (n = 118; log rank P = 0.2). A validation cohort independently confirmed these findings. Conclusions: These results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/terapia , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Gástricas/terapia , Transcriptoma/genética , Adulto , Anciano , Quimioterapia Adyuvante/métodos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Esofagectomía , Esófago/patología , Esófago/cirugía , Femenino , Gastrectomía , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Prospectivos , Medición de Riesgo/métodos , Estómago/patología , Estómago/cirugía , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Resultado del Tratamiento
2.
Clin Oncol (R Coll Radiol) ; 36(1): e11-e19, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37973477

RESUMEN

AIMS: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. MATERIALS AND METHODS: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. RESULTS: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited. FUTURE: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Estradiol , Antagonistas de Andrógenos/uso terapéutico , Andrógenos , Calidad de Vida , Estrógenos , Testosterona
3.
Ann Oncol ; 24(4): 937-43, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23104722

RESUMEN

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS: The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS: The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS: This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.


Asunto(s)
Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Platino (Metal)/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Nomogramas , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Platino (Metal)/efectos adversos , Platino (Metal)/toxicidad , Pronóstico , Sensibilidad y Especificidad , Resultado del Tratamiento
4.
Ann Oncol ; 21(2): 232-237, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19675093

RESUMEN

BACKGROUND: Previous studies reported that women survive longer than men, but experience greater toxicity, when treated for small-cell lung cancer (SCLC). METHODS: Individual patient data from six randomized phase II/III chemotherapy trials, from the Manchester Lung Group and UK Medical Research Council, were pooled for analysis. End points included overall survival, response rate, toxicity, dose intensity (DI) and transfusion rates. RESULTS: Of 1707 patients analyzed, 44% were women. At baseline, women had poorer performance status (PS) (57% versus 67% Eastern Cooperative Oncology Group PS 0-1/Karnofsky PS 80-100, P = 0.0004) and more were of normal weight or underweight (57% versus 48%, P = 0.003), but fewer were anemic (25% versus 62%, P < 0.0001). Response rates between women and men were similar (77% versus 76%, P = 0.64). In univariate [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.76-0.96, P = 0.006] and multivariate (HR 0.88, 95% CI 0.79-0.99, P = 0.04) analyses, female sex predicted for longer survival. Women experienced more grade 3/4 emesis (18% versus 9%, P < 0.0001) and grade 3/4 mucositis (13% versus 8%, P = 0.005) than men. There were no differences in DI, infections, transfusions or treatment-related deaths. CONCLUSION: Data from >1700 patients in randomized SCLC chemotherapy trials confirm that women survive modestly longer than men but may experience greater toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Factores Sexuales , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos como Asunto , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Sociedades Médicas , Análisis de Supervivencia , Resultado del Tratamiento , Reino Unido
5.
Eur J Cancer ; 94: 104-114, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29550565

RESUMEN

BACKGROUND: Oesophageal (OeC) and gastric (GC) cancer patients are treated with similar multimodal therapy and have poor survival. There remains an urgent clinical need to identify biomarkers to individualise patient management and improve outcomes. Therapy with immune checkpoint inhibitors has shown promising results in other cancers. Proposed biomarkers to predict potential response to immune checkpoint inhibitors include DNA mismatch repair (MMR) and/or Epstein-Barr virus (EBV) status. The aim of this study was to establish and compare EBV status and MMR status in large multi-centre series of OeC and GC. METHODS: EBV was assessed by EBV-encoded RNA (EBER) in situ hybridisation and MMR protein expression by immunohistochemistry (IHC) in 988 OeC and 1213 GC from multiple centres. In a subset of OeC, microsatellite instability (MSI) was tested in parallel with MMR IHC. RESULTS: Frequency of MMR deficiency (MMRdef) and MSI was low in OeC (0.8% and 0.6%, respectively) compared with GC (10.3%). None of the OeCs were EBER positive in contrast to 4.8% EBER positive GC. EBV positive GC patients were younger (p = 0.01), more often male (p = 0.001) and had a better overall survival (p = 0.012). MMRdef GC patients were older (p = 0.001) and showed more often intestinal-type histology (p = 0.022). CONCLUSIONS: This is the largest study to date indicating that EBV and MMRdef do not play a role in OeC carcinogenesis in contrast to GC. The potential clinical usefulness of determining MMRdef/EBV status to screen patients for eligibility for immune-targeting therapy differs between OeC and GC patients.


Asunto(s)
Neoplasias Esofágicas/genética , Neoplasias Esofágicas/virología , Neoplasias Gástricas/genética , Neoplasias Gástricas/virología , Adulto , Anciano , Biomarcadores de Tumor/análisis , Reparación de la Incompatibilidad de ADN/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Femenino , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad
6.
J Orthop Surg (Hong Kong) ; 24(2): 170-4, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27574257

RESUMEN

PURPOSE: To compare patient-matched instrumentation (PMI) with conventional total knee arthroplasty (TKA) in terms of limb alignment and component position. METHODS: Nine men and 36 women (mean age, 69.5 years) who underwent PMI TKA were compared with 20 men and 25 women (mean age, 69.3 years) who underwent conventional TKA by the same team of surgeons with the same prosthesis and protocols in terms of limb alignment and component position using the Perth protocol computed tomography, as well as bone resection measurements, operating time, and the number of trays used. RESULTS: The PMI and conventional TKA groups were comparable in terms of age, body mass index, tourniquet time, operating time, and the number of trays used. For limb alignment and component position, the 2 groups differed significantly in sagittal femoral component position (2.4º vs. 0.9º, p=0.0008) and the percentage of knees with femoral component internally rotated ≥1° with respect to the transepicondylar axis (20% vs. 55%, p=0.001). The difference was not significant in terms of limb alignment, coronal and rotational femoral component position, or coronal and sagittal tibial component position. Intra-operatively, all patient-matched cutting blocks demonstrated acceptable fit and stability. No instrument-related adverse events or complications were encountered. One (2.2%) femur and 6 (13.3%) tibiae were recut 2 mm for optimal ligament balancing. Two femoral components were upsized to the next size, and 2 tibial components were upsized and 2 downsized to the next size. CONCLUSION: PMI was as accurate as conventional instrumentation in TKA. There was no significant difference in limb alignment or femoral and tibial component position in the coronal and sagittal planes between PMI and conventional TKA. PMI had a higher tendency to achieve correct femoral component rotation.


Asunto(s)
Artroplastia de Reemplazo de Rodilla/instrumentación , Prótesis de la Rodilla , Osteoartritis de la Rodilla/cirugía , Diseño de Prótesis , Ajuste de Prótesis , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/fisiopatología , Rango del Movimiento Articular , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
8.
Lung Cancer ; 85(2): 116-8, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24908333

RESUMEN

OBJECTIVES: Guidelines for the conduct of clinical trials emphasize the importance of keeping the interim results from the main endpoints confidential, in order to maintain the integrity of the trial and to safeguard patients' interests. However, is this essential in every situation? MATERIALS AND METHODS: We review the evidence for these guidelines and consider recent randomised trials that have released interim results, to assess their impact on the success of the trial. However, because the strength of opinion to keep interim results confidential is so strong, there are limited examples of such trials. RESULTS: In the QUARTZ trial (which is assessing the value of whole brain radiotherapy in patients with brain metastases from non-small cell lung cancer) the decision to release interim results was taken in response to threatened closure due to poor accrual, whereas in the GRIT trial (which compared two obstetric strategies for the delivery of growth retarded pre-term fetuses) the regular release of interim results was pre-planned. Nevertheless there are a number of common factors between these two trials. In particular, the trial treatments were already in wide use, with no reliable randomised evidence on which treatment should be used for which patients, and there was diverse clinical opinion, which meant that accrual was likely to be challenging. In a situation where a quarter to a third of trials do not accrue their required number of patients, the QUARTZ trial continues to accrue patients, and the GRIT trial successfully accrued its target of nearly 600 babies. CONCLUSIONS: This article therefore argues that there is a need to re-consider whether it is always essential to keep the interim results of randomized clinical trials confidential, and suggests some criteria that may help groups planning or running challenging trials decide whether releasing interim results would be a useful strategy.


Asunto(s)
Confidencialidad , Ética en Investigación , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Medicina Basada en la Evidencia , Retardo del Crecimiento Fetal , Guías como Asunto , Humanos , Recien Nacido Prematuro , Ensayos Clínicos Controlados Aleatorios como Asunto/ética , Ensayos Clínicos Controlados Aleatorios como Asunto/normas
9.
Clin Oncol (R Coll Radiol) ; 25(3): e23-30, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23211715

RESUMEN

AIMS: Over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases. If inoperable, optimal supportive care (OSC), including steroids, and whole brain radiotherapy (WBRT) are generally considered to be standard care, although there is no randomised evidence demonstrating that the addition of WBRT to OSC improves survival or quality of life. MATERIALS AND METHODS: QUARTZ is a randomised, non-inferiority, phase III trial comparing OSC + WBRT versus OSC in patients with inoperable brain metastases from NSCLC. The primary outcome measure is quality-adjusted life years (QALYs). QUARTZ was threatened with both loss of funding and early closure due to poor accrual. A lack of preliminary randomised data supporting the trial's hypotheses was thought to underlie the poor accrual, so, with no knowledge of the data, the independent trial steering committee agreed to the unusual step of releasing interim data. RESULTS: Between March 2007 and April 2010, 151 (of the planned 534) patients were randomised (75 OSC + WBRT, 76 OSC). Participants' baseline demographics included median age 67 years (interquartile range 62-73), 60% male, 50% with a Karnofsky performance status <70; steroid usage was similar in the two groups; 64/75 (85%) received WBRT (20 Gy in five fractions). Median survival was: OSC + WBRT 49 days (95% confidence interval 39-61), OSC 51 days (95% confidence interval 27-57) - hazard ratio 1.11 (95% confidence interval 0.80-1.53) in favour of WBRT. Quality of life assessed using EQ-5D showed no evidence of a difference. The estimated mean QALYs was: OSC + WBRT 31 days and OSC 30 days, difference -1 day (95% confidence interval -12.0 to +13.2 days). CONCLUSION: These interim data indicate no early evidence of detriment to quality of life, overall survival or QALYs for patients allocated to OSC alone. They provide key information for discussing the trial with patients and strengthen the argument for continuing QUARTZ to definitively answer this important clinical question.


Asunto(s)
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/radioterapia , Anciano , Neoplasias Encefálicas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Irradiación Craneana/métodos , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Persona de Mediana Edad , Pronóstico , Calidad de Vida , Análisis de Supervivencia , Resultado del Tratamiento
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